1. Field of the Invention
This invention relates to a method for augmenting the inotropic effects of .beta.-adrenergic agonists by co-administering adequate concentrations of pyruvate. The primary target of action for this invention is in stunned or ischemic cardiac tissue. While .beta.-adrenergic agonists are potentially useful in the treatment of inadequate cardiac function in patients, the high concentrations necessary cause undesirable side effects. The use of pyruvate decreases the amount of .beta.-adrenergic agonist necessary to promote stimulation of the cardiac tissue, while decreasing the loss of energy reserves in the muscle, and decreasing oxidative damage to the muscle tissue.
2. Description of the Prior Art
Pyruvate has been recognized as a useful agent in the treatment of patients suffering from cardiac trauma. Stanko (U.S. Pat. No. 5,294,641) teaches a use of pyruvate in patients who suffer from cardiac trauma. The pyruvate may be a pre-treatment to anticipated surgery or administered during surgery. The object of the Stanko invention is to administer pyruvate to increase the cardiac output of a patient in need thereof without concurrently increasing the cardiac oxygen demand of the patient. Others have also disclosed the use of pyruvate in increasing the inotropic function of stunned myocardium. See Bunger et al., Eur. J. Biochem. 180 (1989): 221-233; Mallet et al., Biochim. Biophys. Acta 1224 (1994): 22-32.
Pyruvate has been shown to act as an antioxidant. This could also account for some of the useful characteristics of pyruvate in treating ischemia reperfusion injury. As an .alpha.-keto acid, pyruvate can directly react with H.sub.2 O.sub.2 and lipid peroxides to neutralize these reactive species. Constantopoulos et al., Anal. Biochem. 139 (1984): 353-358. Also, pyruvate can be carboxylated by malic enzyme to generate four-carbon intermediates of the TCA (tricarboxylic acid) cycle, which are converted to citrate by reaction with acetyl CoA. Hiltunen et al., Biochim. Biophys. Acta 678 (1981): 115-121. Russell et al., Am. J. Physiol. 261 (1991): H1756-H1762. Citrate, in turn, can inhibit glycolytic metabolism of glucose, and diverts glucose metabolism to the hexose monophosphate pathway. The malic enzyme reaction and the hexose monophosphate pathway generate nicotinamide adenine diphosphate (NADPH), which reacts with oxidized glutathione disulfide (GSSG) to generate reduced glutathione (GSH), the principle intracellular antioxidant.
A derivative of pyruvate, a pyruvate thiolester, was disclosed by Brunengraber et al. (U.S. Pat. No. 5,667,962) for use in preventing reperfusion injury. Its action in the patient is mostly characterized as an antioxidant, thus diminishing the damaging effects of reactive oxygen species upon ischemia reperfusion.
Likewise, Lucchesi (U.S. Pat. No. 4,048,335) discloses a use of catecholamine derivatives in the inhibition of ischemia reperfusion injury in cardiac tissue. Others have also disclosed the direct use of catecholamines to stimulate function of injured heart muscle. Becker et al., J. Am. Coll. Cardiol. 7 (1986): 580-589; Ellis et al., Am Heart J. 107 (1994): 13-19.
The drawback to the prior inventions is their inability to facilitate the naturally beneficial effects of catecholamines on traumatized heart for clinical uses. Prior disclosures teach only that either pyruvate (Stanko) alone or catecholamines and their chemical derivatives (e.g., Lucchesi) alone can be used to treat inadequately functioning heart. The use of catecholamines and other .beta.-adrenergic agonists alone would be most beneficial, but has the drawback of eliciting deleterious side effects in the patient. On the other hand, use of pyruvate alone, while improving some clinical aspects of ischemic injury, does not have the ideal inotropic effect of a .beta.-adrenergic agonist. Thus, it is desirable to include the benefits of both in a cooperative manner to improve treatment of cardiac trauma.
It is the object of this invention to co-administer .beta.-adrenergic agonists with pyruvate or its derivatives in patients suffering from cardiac trauma. The use of the agonist with pyruvate decreases the amount of agonist necessary to stimulate cardiac contractility, while increasing the energy reserves in the cardiac tissue as well as protecting the tissue from oxidative damage.